Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia

ABSTRACT

Processes for providing depot injections of recrystallized aripiprazole lauroxil in which particles of the aripiprazole lauroxil have a surface area of about 0.50 to about 3.3 m2/g; and crystals of aripiprazole lauroxil produced by such processes.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/595,608, filed Oct. 8, 2019, which is a continuation of U.S.application Ser. No. 16/043,721, filed on Jul. 24, 2018, now U.S. Pat.No. 10,478,434, which is a continuation of U.S. application Ser. No.14/833,638, filed on Aug. 24, 2015, now U.S. Pat. No. 10,064,859, whichapplication claims priority to U.S. Provisional Application 62/041,341,filed on Aug. 25, 2014, the entire contents of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to the preparation of crystallineforms of aripiprazole derivatives including aripiprazole lauroxil andaripiprazole cavoxil. More particularly, the present invention isdirected to controlling the recrystallization of aripiprazole lauroxiland aripiprazole cavoxil to produce particles useful in extended releaseinjectable formulations for the treatment of schizophrenia and otherpsychiatric conditions.

RELATED ART

Aripiprazole is an atypical antipsychotic drug used in the treatment ofschizophrenia and other psychiatric conditions, such as bipolar disorderand major depressive disorder. Aripiprazole, which is a dopamine D₂ andserotonin 5-HT_(1A) receptor agonist, and an antagonist of the serotonin5-HT_(2A) receptor, has been formulated as a tablet and as a solution,both for oral administration. However, concerns with patient compliancewith oral antipsychotics have been reported, and other methods ofdelivering antipsychotics, such as intramuscular or subcutaneousinjection, have been developed.

ABILIFY®, which is a drug containing aripiprazole as the active agent,is available from Otsuka as an oral tablet (aripiprazole dosage of 2 mg,5 mg, 10 mg, 15 mg, 20 mg, or 30 mg), an orally disintegrating tablet(dosage of 10 mg or 15 mg), an oral solution (dosage of 1 mg/mL), and asan injection for intramuscular use (9.75 mg/1.3 mL in a single-dosevial). ABILIFY® is indicated for schizophrenia, bipolar I disorder,adjunctive treatment of major depressive disorder, irritabilityassociated with autistic disorder, and agitation associated withschizophrenia or bipolar mania. Abilify Maintena® is an extended releaseinjectable suspension of aripiprazole available from Otsuka, and whichis indicated for schizophrenia.

There is a need in the art for formulations containing an aripiprazoleprodrug that when administered to a patient can provide for improvedtherapeutic amounts of aripiprazole. There is also a need in the art formethods of preparing an aripiprazole prodrug that can be formulated intoa long-acting or extended-release formulation that when administered toa patient can provide for improved therapeutic amounts of aripiprazoleover an extended period of time.

SUMMARY OF THE INVENTION

The present invention provides a process for making a compound ofFormula (A) in crystal form

wherein R^(a) is CH₂OC(O)R¹ and wherein R¹ is a substituted orunsubstituted aliphatic moiety,

comprising the steps of:

-   -   (a) obtaining a drug solution by combining the compound of        Formula (A) or a salt or solvate thereof with a first solvent;    -   (b) optionally combining the drug solution with a second solvent        to form a mixture;    -   (c) cooling the mixture; and    -   (d) when the temperature of the mixture is within the range of        about 0-5° C. above a target temperature, homogenizing the        mixture to form crystallized particles of the compound of        Formula (A) having a surface area of about 0.50 m²/g to about        3.3 m²/g.

In another embodiment of the method, the compound of Formula (A) isselected from the group consisting of:

In a particular embodiment of the method, the compound of Formula (A)has the structure of Formula (I). In another particular embodiment, thecompound of Formula (A) has the structure of Formula (II).

The present invention provides a process for making a compound ofFormula (I) in crystal form

comprising the steps of:

-   -   (a) obtaining a drug solution by combining the compound of        Formula (A) or a salt or solvate thereof with a first solvent;    -   (b) optionally combining the drug solution with a second solvent        to form a mixture;    -   (c) cooling the mixture; and    -   (d) when the temperature of the mixture is within the range of        about 0-5° C. above a target temperature, homogenizing the        mixture to form crystallized particles of the compound of        Formula (A) having a surface area of about 0.50 m²/g to about        3.3 m²/g.

The present invention also provides a process for making a compound ofFormula (II) in crystal form

comprising the steps of:

-   -   (a) obtaining a drug solution by combining the compound of        Formula (A) or a salt or solvate thereof with a first solvent;    -   (b) optionally combining the drug solution with a second solvent        to form a mixture;    -   (c) cooling the mixture; and    -   (d) when the temperature of the mixture is within the range of        about 0-5° C. above a target temperature, homogenizing the        mixture to form crystallized particles of the compound of        Formula (A) having a surface area of about 0.50 m²/g to about        3.3 m²/g.

The processes provided herein encompass a number of embodiments,including the following:

In one embodiment, the first solvent of step (a) is a single solvent. Inanother embodiment, the first solvent of step (a) is a mixture of two ormore solvents. In a particular embodiment, the first solvent of step (a)is a mixture of two or more solvents and step (b) is absent. Suitablesolvents are known to persons having skill in the art ofcrystallization. Examples of solvents are provided infra. In aparticular embodiment, the first solvent of step (a) is isopropylacetate. In another particular embodiment, the first solvent of step (a)is a mixture of isopropyl acetate and n-heptane.

In one embodiment, step (b) comprises combining the drug solution with asecond solvent to form a mixture. In a particular embodiment, the secondsolvent of step (b) is n-heptane. The mixture of step (b) may be ahomogeneous mixture. In certain embodiments, homogeneity of the mixtureof step (b) is achieved or maintained by heating or preheating the firstsolvent of step (a) and/or the drug solution of step (a) and/or thesecond solvent of step (b). In a particular embodiment, the temperatureof the mixture of step (b) is in the range of about 55° C. to about 65°C. In another embodiment, step (b) is absent. When step (b) is absent,step (c) comprises cooling the drug solution of step (a), and step (d)comprises homogenizing the drug solution to form crystallized particlesof the compound of Formula (A) having a surface area of about 0.50 m²/gto about 3.3 m²/g when the temperature of the mixture is within therange of about 0-5° C. above a target temperature,

In one embodiment, step (c) comprises cooling the mixture to the pointof supersaturation. The temperature at which the mixture becomessupersaturated may be in the range of about 50° C. to about 55° C. Inanother embodiment, step (c) comprises cooling to mixture to so that itstemperature approaches a target temperature. In a particular embodiment,the target temperature is about 34° C.

In one embodiment, the target temperature of step (d) is in the range ofabout 31° C. to about 35° C. In a particular embodiment, the targettemperature of step (d) is about 34° C.

In another embodiment of step (d), homogenizing begins when thetemperature of the mixture is about 0° C. to about 4° C. above thetarget temperature (e.g., at about 31° C. to about 38° C.).

The foregoing methods may further comprise the following steps:

-   -   (e) stopping homogenization and re-dissolving the crystallized        particles of the compound of Formula (A) (e.g., compounds having        the structure of Formula (I) or Formula (II)) by heating the        mixture;    -   (f) cooling the mixture; and    -   (g) when the temperature of the mixture is within the range of        about 0-5° C. above the target temperature, homogenizing the        mixture to form crystallized particles of the compound of        Formula (A) (e.g., compounds having the structure of Formula (I)        or Formula (II)) having a surface area of about 0.50 m²/g to        about 3.3 m²/g.

Steps (c), (d) and (e) may be performed once, or two or more times,prior to proceeding to step (f).

Any one or more of steps (a), (b), (c), (d), (e), and (f) may beperformed under agitation

The foregoing methods may further comprise the following steps:filtering the crystallized particles; rinsing the crystallizedparticles; and drying the crystallized particles.

The crystallized particles produced in accordance with the processesdescribed herein may have a surface area of about 0.80 to about 1.1m²/g. In one embodiment, the crystallized particles have a surface areaof about 1.00 m²/g. In another embodiment, the Dv[50] of thecrystallized particles is about 10 to about 30 microns. In still anotherembodiment, the Dv[50] of the crystallized particles is about 10 toabout 20 microns. In yet another embodiment, the crystallized particlesare suitable for use in a depot injection.

The invention provides crystallized particles of the compound of Formula(I) and the compound of Formula (II) produced by the foregoing process.Preferably, the crystallized particles may have a surface area of about0.80 to about 1.1 m²/g, and more preferably, about 1.00 m²/g. The Dv[50]of the crystallized particles may be about 10 to about 30 microns,preferably about 10 to about 20 microns.

The present invention provides a process for providing a depot injectioncomprising the compound of Formula (I) in crystal form

the process comprising the steps of (a) obtaining a drug solution bycombining the compound of Formula (I) or a salt or solvate thereof witha first solvent; (b) combining the drug solution with a second solventto form a mixture with reduced solubility relative to the solubility ofthe drug solution; (c) cooling the mixture so that it becomessupersaturated; (d) cooling the mixture so that its temperatureapproaches a target temperature; and (e) when the temperature of themixture is within the range of about 5° C. above the target temperature,homogenizing the mixture to form crystallized particles of the compoundof Formula (I) having a surface area of about 0.50 to about 3.3 m²/g.Any one or more of steps (a) through (d) of the foregoing process may beperformed under agitation. The foregoing process may further comprisethe steps of (f) filtering the crystallized particles, (g) rinsing thecrystallized particles, and (h) drying the crystallized particles.

In the foregoing process, the first solvent may be ethyl acetate, propylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butylacetate, acetone, and the like, with isopropyl acetate being preferred;and the second solvent may be pentane, cyclopentane, hexane,cyclohexane, methyl cyclohexane, heptanes, octane, nonane, decane,undecane, dodecane, ethanol, methanol, and the like, with n-heptanebeing preferred.

Preferably, in step (b), the temperature of the mixture is in the rangeof about 55° C. to about 65° C. In step (c), the temperature at whichthe mixture becomes supersaturated may be in the range of about 50° C.to about 55° C. The target temperature reached in step (d) may be in therange of about 31° C. to about 35° C., such as about 34° C. Preferably,in step (e), the homogenizing begins when the temperature of the mixtureis about 0° C. to about 4° C. above the target temperature.

The invention also provides for crystallized particles of the compoundof Formula (I) produced by the foregoing process. Preferably, thecrystallized particles may have a surface area of about 0.80 to about1.1 m²/g, and more preferably, about 1.00 m²/g. The Dv[50] of thecrystallized particles may be about 10 to about 30 microns, preferablyabout 10 to about 20 microns.

Further, the invention provides a process for providing a depotinjection comprising the compound of Formula (I) in crystal form

the process comprising the steps of (a) obtaining a drug solution bycombining the compound of Formula (I) or a salt or solvate thereof withheated isopropyl acetate; (b) combining the drug solution with n-heptaneto form a mixture with reduced solubility relative to the solubility ofthe drug solution; (c) cooling the mixture so that it becomessupersaturated; (d) cooling the mixture so that its temperatureapproaches a target temperature of about 34° C.; and (e) when thetemperature of the mixture is within the range of about 5° C. above thetarget temperature, homogenizing the mixture to form crystallizedparticles of the compound of Formula (I) having a surface area of about0.50 to about 3.3 m²/g. Any one or more of steps (a) through (d) of theforegoing process may be performed under agitation. The foregoingprocess may further comprise the steps of (f) filtering the crystallizedparticles, (g) rinsing the crystallized particles, and (h) drying thecrystallized particles.

Preferably, in step (b), the temperature of the mixture is in the rangeof about 55° C. to about 65° C. In step (c), the temperature at whichthe mixture becomes supersaturated may be in the range of about 50° C.to about 55° C. The target temperature reached in step (d) may be in therange of about 31° C. to about 35° C., such as about 34° C. Preferably,in step (e), the homogenizing begins when the temperature of the mixtureis about 0° C. to about 4° C. above the target temperature.

The invention also provides for crystallized particles of the compoundof Formula (I) produced by the foregoing process. Preferably, thecrystallized particles may have a surface area of about 0.80 to about1.1 m²/g, and more preferably, about 1.00 m²/g. The Dv[50] of thecrystallized particles may be about 10 to about 30 microns, preferablyabout 10 to about 20 microns.

Still further, the invention provides a process for providing a depotinjection comprising the compound of Formula (I) in crystal form

the process comprising the steps of (a) obtaining a drug solution bycombining the compound of Formula (I) or a salt or solvate thereof witha first solvent; (b) combining the drug solution with a second solventto form a mixture with reduced solubility relative to the solubility ofthe drug solution; (c) cooling the mixture so that it becomessupersaturated; (d) cooling the mixture so that its temperatureapproaches a target temperature; (e) when the temperature of the mixtureis within the range of about 5° C. above the target temperature,homogenizing the mixture to form crystallized particles of the compoundof Formula (I); (f) stopping homogenization, and re-dissolving thecrystallized particles of the compound of Formula (I) by heating themixture; (g) cooling the mixture so that its temperature approaches thetarget temperature; and (h) when the temperature of the mixture iswithin the range of about 5° C. above the target temperature,homogenizing the mixture to form crystallized particles of the compoundof Formula (I) having a surface area of about 0.50 to about 3.3 m²/g.

Steps (d), (e), and (f) of the foregoing process can be performed asecond time (or three times, four times, etc.) prior to proceeding tostep (g). For example, the process steps can be carried out in the order(a), (b), (c), (d), (e), (f), (d), (e), (f), (g), and (h); that is,steps (d) through (f) are performed twice in succession.

In the foregoing process, the first solvent may be ethyl acetate, propylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butylacetate, acetone, and the like, with isopropyl acetate being preferred;and the second solvent may be pentane, cyclopentane, hexane,cyclohexane, methyl cyclohexane, heptanes, octane, nonane, decane,undecane, dodecane, ethanol, methanol, and the like, with n-heptanebeing preferred.

Any one or more of steps (a), (b), (c), (d), (e), (f), and (g) of theforegoing process may be performed under agitation. The foregoingprocess may further comprise the steps of (i) filtering the crystallizedparticles, (j) rinsing the crystallized particles, and (k) drying thecrystallized particles.

Preferably, in step (b), the temperature of the mixture is in the rangeof about 55° C. to about 65° C. In step (c), the temperature at whichthe mixture becomes supersaturated may be in the range of about 50° C.to about 55° C. The target temperature reached in steps (d) and (g) maybe in the range of about 31° C. to about 35° C., such as about 34° C.Preferably, in steps (e) and (h), the homogenizing begins when thetemperature of the mixture is about 0° C. to about 4° C. above thetarget temperature.

The invention also provides for crystallized particles of aripiprazolelauroxil produced by the foregoing process. Preferably, the crystallizedparticles may have a surface area of about 0.80 to about 1.1 m²/g, andmore preferably, about 1.00 m²/g. The Dv[50] of the crystallizedparticles may be about 10 to about 30 microns, preferably about 10 toabout 20 microns.

In alternative embodiments, the homogenizing of the processes describedherein can be replaced with sonicating or the use of an ultrasounddevice.

The depot injection provided by any of the foregoing processes canprovide for extended release of aripiprazole in vivo. Such extendedrelease can occur, for example, over from a period of about one month toa period of about three months. Preferably, such extended release canoccur, for example, over from a period of about one month to a period ofabout two months. The depot injection provided by any of the foregoingprocesses can be administered, for example, as a once-monthly injection,a once-every-two-months injection, or a once-every-three monthsinjection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a typical cooling profile for the recrystallizationprocess of the present invention.

FIG. 2 is a graph showing that homogenizer initiation inducedcrystallization of aripiprazole lauroxil at a target temperature.

FIG. 3 depicts temperature profiles for recrystallization tests at the 4kg scale.

FIG. 4 is a graph showing the relationship between surface area ofparticles of recrystallized aripiprazole lauroxil and exotherm onsettemperature.

FIG. 5 is a graph showing the relationship between particle size andsurface area.

FIGS. 6, 7, 8, 9, and 10 show models built from the results of anaugmented multi-factor DOE study used to evaluate the combinatory effectof homogenizer initiation temperature, homogenizer speed, and heattransfer temperature gradient on in-process crystal surface area,particle size, and exotherm onset temperature.

FIG. 11 shows the relationship between surface area of particles ofrecrystallized aripiprazole lauroxil and exotherm onset temperature asrevealed by an augmented multi-factor DOE study.

FIG. 12 shows several cooling profiles for runs from a multi-factor DOE(central composite design) study that used no homogenization.

FIG. 13 shows plots of transformed temperature data for the coolingprofiles from FIG. 12 .

FIG. 14 shows a plot of exotherm onset temperature (Tmin) versus thecalculated Exponential Primary Cooling Parameter (i.e., cooling rate).

FIG. 15 shows particle size distributions for several batches ofrecrystallized aripiprazole lauroxil made according to a 200 gramprocess.

FIG. 16 shows particle size distributions for several batches ofrecrystallized aripiprazole lauroxil made according to a modified 200gram process.

FIG. 17 shows aripiprazole pK profiles resulting from intramuscularadministration of a single dose of recrystallized aripiprazole lauroxil(20 mg aripiprazole equivalents) suspended in either NaCMC or SMLvehicle, to male rats to assess the effect of injection vehicle on thein vivo profile.

FIG. 18 shows particle size distribution (PSD) profiles for four lots ofaripiprazole lauroxil recrystallized drug substance.

FIG. 19 shows aripiprazole pK profiles resulting from IM administrationto male rats of recrystallized aripiprazole lauroxil from the same lotsas in FIG. 18 suspended in SML vehicle.

DETAILED DESCRIPTION

Crystallization

Crystallization is a process of forming crystals through precipitationof solids from a solution, which occurs by variation of the solubilityconditions of the solute in the solvent. The process is governed by boththermodynamic and kinetic factors, which can make it highly variable anddifficult to control. These factors include component concentrations,impurity levels, mixing regime, vessel design, and cooling profile. Allcan have a major impact on the size, number, and shape of crystalsproduced.

Thermodynamically, crystallization is impossible below the theoreticalsolution solubility threshold (saturation). At values above thisthreshold, the solution is supersaturated (contains more solute thancould be dissolved by the solvent under normal circumstances) andcrystallization may proceed. Supersaturation is a fundamental factor incrystallization dynamics, where the level of supersaturation affects thecrystallization rate and indicates that crystallization is underkinetic, rather than thermodynamic, control.

Crystallization consists of two major kinetic driven events: nucleationand crystal growth. Nucleation is the step where the solute moleculesdispersed in the solvent start to gather into clusters (nuclei) thatbecome stable under the current operating conditions. The crystal growthis the subsequent growth of the nuclei that succeed in producing stablecrystals. Nucleation and growth continue to occur simultaneously whilesolution supersaturation exists.

Nucleation is the initiation of crystallization and is the sum effect oftwo categories, primary and secondary. Primary nucleation is the initialformation of nuclei where there are no other crystals present. Thistypically occurs through the influence/presence of other solids (i.e.,walls of the crystallizer vessel and particles of any foreignsubstance). Secondary nucleation is the formation of nuclei attributableto the influence of already-existing crystals in the solution.Typically, this is a function of fluid shear and collisions of crystalsand results in the formation of new nuclei. Several factors used toinfluence nucleation rate are use of seed crystals, equipment surfaceimperfections, and high shear homogenization.

The combination of solution supersaturation level and factors such ashomogenization governs the nucleation rate, which in turn influences thecrystal particle size and surface area. In general, a fast nucleationrate leads to smaller crystals, while a slow nucleation results inlarger crystals. This is best understood through the concept ofpopulation balance. A fast nucleation rate creates a large number ofsmall nuclei in a specified period, while a slow nucleation rate createsa lesser number in the same period. After the nuclei are generated, theythen being to grow. Given a finite amount of mass available for growth,and assuming equivalent growth rates, the larger number population ofnuclei will achieve a final particle size that is smaller (converselylarger surface area) than the lesser number population.

Aripiprazole Lauroxil

Aripiprazole lauroxil, an N-lauroyloxymethyl prodrug form ofaripiprazole, has been developed for formulation into extended-releaseinjectable formulations, such as for intramuscular injection.Aripiprazole lauroxil is a non-hygroscopic white crystalline solid witha melting point of 81.3 to 83.0° C., and it exists as a stable form,which has not been observed in any polymorphic modifications to date.The compound is insoluble in water (<4 ng/mL at room temperature) andshows highest room temperature solubility in the following organicsolvents: TH (˜400 mg/mL), dichloromethane (˜500 mg/mL), and toluene(˜300 mg/mL). The IUPAC name for aripiprazole lauroxil is(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyldodecanoate, corresponding to the molecular formula C₃₆H₅₁Cl₂N₃O₄ and amolecular weight of 660.7. Aripiprazole lauroxil may also be referred toas N-lauroyloxymethyl aripiprazole. The chemical structure ofaripiprazole lauroxil is as follows:

and is also referred to herein as Formula (I).

Pre-processed aripiprazole lauroxil suitable for the recrystallizationprocess described herein may be obtained, for example, by following thesynthesis described in U.S. Pat. No. 8,431,576. This document isincorporated herein by reference in its entirety. Salts and solvates ofaripiprazole lauroxil, which are disclosed and described in U.S. Pat.No. 8,431,576, are also suitable for the recrystallization processdescribed herein.

Aripiprazole lauroxil undergoes hydrolysis to lauric acid, formaldehyde,and aripiprazole, which is an important antipsychotic used in thetreatment of schizophrenia and other psychiatric conditions, such asbipolar disorder and major depressive disorder. Conversion ofaripiprazole lauroxil to aripiprazole in vivo is governed by slowdissolution of the aripiprazole lauroxil drug crystals and subsequentenzyme-mediated cleavage to the N-hydroxymethyl aripiprazoleintermediate, which spontaneously converts to aripiprazole.

The slow dissolution of the aripiprazole lauroxil drug crystals in vivoresults in systemic exposure of aripiprazole over several weeks. Therate of aripiprazole lauroxil release is a function of the amount ofexposed surface area, represented by particle size distribution (PSD)and shape/morphology of the drug crystals.

An extended release IM injection offers the potential for an improvedsafety profile and treatment compliance; therefore, it has the potentialto provide more effective management of schizophrenia.

The present invention provides a process for providing a depot injectioncomprising aripiprazole lauroxil, i.e., the compound of Formula (I), incrystal form.

The process comprises the steps of: (a) obtaining a drug solution bycombining the compound of Formula (I) or a salt or solvate thereof witha first solvent; (b) combining the drug solution with a second solventto form a mixture with reduced solubility relative to the solubility ofthe drug solution; (c) cooling the mixture so that it becomessupersaturated; (d) cooling the mixture so that its temperatureapproaches a target temperature; and (e) when the temperature of themixture is within the range of about 5° C. above the target temperature,homogenizing the mixture to form crystallized particles of the compoundof Formula (I) having a surface area of about 0.50 to about 3.3 m²/g.Any one or more of steps (a) through (d) of the foregoing process may beperformed under agitation. The foregoing process may further comprisethe steps of (f) filtering the crystallized particles, (g) rinsing thecrystallized particles, and (h) drying the crystallized particles.

In the foregoing process, the first solvent may be ethyl acetate, propylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butylacetate, acetone, and the like, with isopropyl acetate being preferred;and the second solvent may be pentane, cyclopentane, hexane,cyclohexane, methyl cyclohexane, heptanes, octane, nonane, decane,undecane, dodecane, ethanol, methanol, and the like, with n-heptanebeing preferred.

Preferably, in step (b), the temperature of the mixture is in the rangeof about 55° C. to about 65° C. In step (c), the temperature at whichthe mixture becomes supersaturated may be in the range of about 50° C.to about 55° C. The target temperature reached in step (d) may be in therange of about 31° C. to about 35° C., such as about 34° C. Preferably,in step (e), the homogenizing begins when the temperature of the mixtureis about 0° C. to about 4° C. above the target temperature.

The homogenizing in step (e) initializes and promotes crystallization,and allows for control of particle size and surface area. A suitablehomogenization speed is from about 4800 to about 9600 rpm. The drying instep (h) can be conducted under nitrogen purge and vacuum.

The invention also provides for crystallized particles of the compoundof Formula (I) produced by the foregoing process. Preferably, thecrystallized particles may have a surface area of about 0.80 to about1.1 m²/g, and more preferably, about 1.00 m²/g. The Dv[50] of thecrystallized particles may be about 10 to about 30 microns, preferablyabout 10 to about 20 microns.

Further, the invention provides a process for providing a depotinjection comprising the compound of Formula (I) in crystal form

the process comprising the steps of (a) obtaining a drug solution bycombining the compound of Formula (I) or a salt or solvate thereof withheated isopropyl acetate; (b) combining the drug solution with n-heptaneto form a mixture with reduced solubility relative to the solubility ofthe drug solution; (c) cooling the mixture so that it becomessupersaturated; (d) cooling the mixture so that its temperatureapproaches a target temperature of about 34° C.; and (e) when thetemperature of the mixture is within the range of about 5° C. above thetarget temperature, homogenizing the mixture to form crystallizedparticles of the compound of Formula (I) having a surface area of about0.50 to about 3.3 m²/g. Any one or more of steps (a) through (d) of theforegoing process may be performed under agitation. The foregoingprocess may further comprise the steps of (f) filtering the crystallizedparticles, (g) rinsing the crystallized particles, and (h) drying thecrystallized particles.

Preferably, in step (b), the temperature of the mixture is in the rangeof about 55° C. to about 65° C. In step (c), the temperature at whichthe mixture becomes supersaturated may be in the range of about 50° C.to about 55° C. The target temperature reached in step (d) may be in therange of about 31° C. to about 35° C., such as about 34° C. Preferably,in step (e), the homogenizing begins when the temperature of the mixtureis about 0° C. to about 4° C. above the target temperature.

The homogenizing in step (e) initializes and promotes crystallization,and allows for control of particle size and surface area. A suitablehomogenization speed is from about 4800 to about 9600 rpm. The drying instep (h) can be conducted under nitrogen purge and vacuum.

The invention also provides for crystallized particles of the compoundof Formula (I) produced by the foregoing process. Preferably, thecrystallized particles may have a surface area of about 0.80 to about1.1 m²/g, and more preferably, about 1.00 m²/g. The Dv[50] of thecrystallized particles may be about 10 to about 30 microns, preferablyabout 10 to about 20 microns.

Still further, the invention provides a process for providing a depotinjection comprising the compound of Formula (I) in crystal form

the process comprising the steps of (a) obtaining a drug solution bycombining the compound of Formula (I) or a salt or solvate thereof witha first solvent; (b) combining the drug solution with a second solventto form a mixture with reduced solubility relative to the solubility ofthe drug solution; (c) cooling the mixture so that it becomessupersaturated; (d) cooling the mixture so that its temperatureapproaches a target temperature; (e) when the temperature of the mixtureis within the range of about 5° C. above the target temperature,homogenizing the mixture to form crystallized particles of the compoundof Formula (I); (f) stopping homogenization, and re-dissolving thecrystallized particles of the compound of Formula (I) by heating themixture; (g) cooling the mixture so that its temperature approaches thetarget temperature; and (h) when the temperature of the mixture iswithin the range of about 5° C. above the target temperature,homogenizing the mixture to form crystallized particles of the compoundof Formula (I) having a surface area of about 0.50 to about 3.3 m²/g.

Steps (d), (e), and (f) of the foregoing process can be performed asecond time (or three times, four times, etc.) prior to proceeding tostep (g). For example, the process steps can be carried out in the order(a), (b), (c), (d), (e), (f), (d), (e), (f), (g), and (h); that is,steps (d) through (f) are performed twice in succession.

In the foregoing process, the first solvent may be ethyl acetate, propylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butylacetate, acetone, and the like, with isopropyl acetate being preferred;and the second solvent may be pentane, cyclopentane, hexane,cyclohexane, methyl cyclohexane, heptanes, octane, nonane, decane,undecane, dodecane, ethanol, methanol, and the like, with n-heptanebeing preferred.

Any one or more of steps (a), (b), (c), (d), (e), (f), and (g) of theforegoing process may be performed under agitation. The foregoingprocess may further comprise the steps of (i) filtering the crystallizedparticles, (j) rinsing the crystallized particles, and (k) drying thecrystallized particles.

Preferably, in step (b), the temperature of the mixture is in the rangeof about 55° C. to about 65° C. In step (c), the temperature at whichthe mixture becomes supersaturated may be in the range of about 50° C.to about 55° C. The target temperature reached in steps (d) and (g) maybe in the range of about 31° C. to about 35° C., such as about 34° C.Preferably, in steps (e) and (h), the homogenizing begins when thetemperature of the mixture is about 0° C. to about 4° C. above thetarget temperature.

The homogenizing in steps (e) and (h) initializes and promotescrystallization, and allows for control of particle size and surfacearea. A suitable homogenization speed is from about 4800 to about 9600rpm. The drying in step (k) can be conducted under nitrogen purge andvacuum.

The invention also provides for crystallized particles of the compoundof Formula (I) produced by the foregoing process. Preferably, thecrystallized particles may have a surface area of about 0.80 to about1.1 m²/g, and more preferably, about 1.00 m²/g. The Dv[50] of thecrystallized particles may be about 10 to about 30 microns, preferablyabout 10 to about 20 microns.

Each of the foregoing processes may use, instead of the compound ofFormula (I), a salt or solvate thereof such as the salts or solvates ofpre-processed aripiprazole lauroxil disclosed and described in U.S. Pat.No. 8,431,576.

Aripiprazole Cavoxil

Aripiprazole cavoxil, an N-hexanoyloxymethyl prodrug form ofaripiprazole, has been developed for formulation into extended-releaseinjectable formulations, such as for intramuscular injection. The IUPACname for aripiprazole cavoxil is(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylhexanoate, corresponding to the molecular formula C₃₀H₃₉Cl₁₂N₃O₄ and amolecular weight of 576.56. The chemical structure of aripiprazolecavoxil is as follows.

and is also referred to herein as Formula (II). Aripiprazole cavoxilsuitable for the processes described herein may be obtained, forexample, by the synthesis methods described in U.S. Pat. No. 8,431,576.This document is incorporated herein by reference in its entirety. Saltsand solvates of aripiprazole cavoxil, which are disclosed and describedin U.S. Pat. No. 8,431,576, are also suitable for the processesdescribed herein.

Process Equipment

The following process equipment was used to recrystallize aripiprazolelauroxil according to the present invention. Other suitable processequipment may be used, as would be well understood by one skilled in theart in light of present disclosure.

Drug dissolution vessel: To produce a 4.0 kg batch of recrystallizedaripiprazole lauroxil, a single closed, jacketed, agitated 20 litervessel was used to dissolve and transfer the drug through a sterilizingfilter to the sterilized recrystallization vessel in a single step. Asmaller pilot process (producing 1.75 kg of recrystallized aripiprazolelauroxil) used two small stock pots and hot plates to dissolve the drug,and multiple transfer steps to a 4 liter pressure vessel to sterilefilter the solution into the recrystallization vessel. At both 4.0 kgand 1.75 kg scales, warm isopropyl acetate was used to dissolve thepre-processed drug crystals of aripiprazole lauroxil. As would be wellunderstood by one of skill in the art, a “jacket” refers to heattransfer fluid and to the encased space around the vessel containing theheat transfer fluid that acts as a heat exchanger to cool or heat theinside of the vessel, and a “glycol jacket” is a jacket where the heattransfer fluid is glycol or a mixture of water and glycol. The glycoljacket temperature affects primary cooling, which transitions the systeminto a meta-stable zone where crystallization of aripiprazole lauroxilcan be initiated with homogenization.

Drug solution filter: The drug solution filter used for both scales wasMilliport Aervent OptiSeal Cartridge, PTFE Hydrophobic, LAGR04TP6(112-00783).

Filter heat tape: The filter heat tape used for both scales wasFiberglass Cloth Heating Tape with Glas-Col PowrTrol Controller (10amps/120 volts).

Recrystallization vessel: The recrystallization vessel used for bothscales was a DCI 24-Liter Cone Shaped (16″ upper ID/23 angle) StainlessSteel Jacketed Vessel (DCI Serial #: JS2884) with a 3.75″ Radial LowerImpeller, 3.75″ Axial Upper Impeller on an angled (non-vertical)agitator.

Homogenizer: The homogenizer used for both scales was a KinematicaPolytron PT-D 50-6 F/G (installed in the recrystallization vessel) with50 mm Stator Diameter and 45 mm Rotor Diameter.

Sonicator: An exemplary sonicator suitable for use with the process ofthe present invention is Transsonic T310 from Lab-Line Instruments Inc.

Dryer: The dryer used in the 4.0 kg scale process was a closed,agitated, 15″ self-discharging vacuum filter dryer (Powder SystemsLimited; PSL). The 1.75 kg scale process used two 8″ static vacuumfilter dryers that required manual aseptic stirring of therecrystallized drug crystals prior to drying and discharge. The mode ofdrying was the same at both scales, namely, the recrystallized drugcrystals were dried under vacuum at room temperature with a dry gaspurge to facilitate removal of processing solvents to acceptably lowlevels.

Filtrate vessel: The filtrate vessel used in both scales was a DCI10-gallon Stainless Steel Jacketed Vessel (DCI Serial #: JS2060).

Recrystallization Process

The recrystallization process of the present invention can producecrystallized particles of aripiprazole lauroxil having a surface area ofabout 0.50 to about 3.3 m²/g, preferably about 0.80 to about 1.1 m²/g,more preferably about 1.00 m²/g. The Dv[50] of the crystallizedparticles may be about 10 to about 30 microns, preferably about 10 toabout 20 microns.

Recrystallized aripiprazole lauroxil can be produced through thefollowing procedure:

Drug Dissolution: Dissolve pre-processed aripiprazole lauroxil or a saltor solvate thereof in a first solvent such as isopropyl acetate oranother suitable first solvent as described herein, and sterile filterthe result into a recrystallization vessel.

Crystallization: Mix the drug solution (aripiprazole lauroxil dissolvedin, e.g., isopropyl acetate) and a second solvent such as heptane oranother suitable second solvent as described herein and then cool at acontrolled rate; initiate homogenization at a target temperature toinduce crystallization.

Collection: Transfer contents of recrystallization vessel and filtercrystals from the solvent in a dryer.

Rinsing: Use a fresh portion of the second solvent to recover anycrystals remaining in the recrystallization vessel and remove grossresidual first solvent from the crystal surface.

Rinsing can also remove residual amounts of acetonitrile, which may havebeen present in the pre-processed aripiprazole lauroxil.

Drying: Use vacuum drying to reduce levels of both the first and secondsolvents.

The first solvent may be ethyl acetate, propyl acetate, isopropylacetate, butyl acetate, isobutyl acetate, tert-butyl acetate, acetone,or another suitable solvent as would be well understood by one skilledin the art in light of the present disclosure, or mixtures of theforegoing solvents. Isopropyl acetate is a preferred first solvent.

The second solvent may be pentane, cyclopentane, hexane, cyclohexane,methyl cyclohexane, heptanes, octane, nonane, decane, undecane,dodecane, ethanol, methanol, or another suitable solvent as would bewell understood by one skilled in the art in light of the presentdisclosure, or mixtures of the foregoing solvents. N-heptane is apreferred second solvent.

A preferred selection and ratio of first solvent and second solvent isisopropyl acetate and heptanes, in a ratio of 1:2 (v/v).

When the drug solution of aripiprazole lauroxil in a first solvent (suchas isopropyl acetate) is combined with the second solvent (such asheptane), this forms a mixture with reduced solubility relative to thesolubility of the drug solution. The drug solution and the secondsolvent are preferably combined at a temperature of from about 55° C. toabout 65° C., and then the mixture is cooled at a specified rate, suchas 1.5° C. per minute, so that the mixture becomes supersaturated. Thetemperature at which the mixture becomes supersaturated may be in therange of about 50° C. to about 55° C.

Then the mixture is cooled so that its temperature approaches a targettemperature. This target temperature may be in the range of about 31° C.to about 35° C., such as about 34° C. When the temperature of themixture is within the range of about 0° C. to about 4° C. above thetarget temperature, homogenization of the mixture is initiated. Asuitable speed for homogenization is from about 4800 to about 9600 rpm.

Drug dissolution, combining the drug solution and the second solvent,cooling the mixture of the drug solution and the second solvent, coolingthe mixture once it has become supersaturated, homogenizing the mixture,and re-dissolving the crystallized particles of aripiprazole lauroxil byheating the mixture can each be performed under agitation. The agitationmay be carried out with an agitator such as an overhead stirrer. Theagitator helps to maintain a uniform crystal suspension and control overthe temperature.

Suitable salts and solvates of pre-processed aripiprazole lauroxil thatcan be obtained, synthesized, and used with the present inventioninclude those disclosed in U.S. Pat. No. 8,431,576.

Formulations

The recrystallized aripiprazole lauroxil prepared according to themethods disclosed herein can be suspended in injection vehicles toproduce injectable compositions suitable, for example, for IMadministration. Such vehicles include a phosphate-buffered salineinjection vehicle comprising sorbitan monolaurate in an amount ofapproximately 0.37% by weight relative to the weight of the injectablecomposition; polysorbate 20 in an amount of approximately 0.15% byweight relative to the weight of the injectable composition; and anaqueous carrier. The recrystallized aripiprazole lauroxil preparedaccording to the methods disclosed herein can also be incorporated intoother vehicles and formulations, such as those disclosed in U.S. PatentApplication Publication No. 2012/0238552.

The following is the formulation of an exemplary depot injectioncomposition comprising recrystallized aripiprazole lauroxil preparedaccording to the methods disclosed herein:

Amount Per Formulation Dose (% w/w) Recrystallized Aripiprazole 26.6  Lauroxil Drug Substance Sorbitan Monolaurate 0.37 Polysorbate 20 0.15Sodium Chloride 0.59 CMC NA Sodium Phosphate Dibasic 0.06 AnhydrousSodium Dihydrogen Phosphate 0.05 Monobasic Dihydrate Water for InjectionQS to 100

Relation of Particle Size and Release Rate

Particle size of the aripiprazole lauroxil produced from therecrystallization process of the present invention was shown to relateto release rate in animal studies and thus required controlling towithin an acceptable range. The particle size distribution (PSD) ofrecrystallized aripiprazole lauroxil produced according to the processdisclosed herein can be measured, for example, using a light scatteringparticle size analyzer such as those available from HORIBA orBeckman-Coulter, or by other suitable instruments and methods as wouldbe well understood by one skilled in the art in light of the presentdisclosure.

As used herein, “Dv[50]” refers to the 50th percentile of the particlesize distribution, which is interchangeable with median diameter or theaverage particle diameter by volume. As used herein, “Dv[10]” refers tothe 10th percentile of the particle size distribution, “Dv[90]” refersto the 90th percentile of the particle size distribution, and “Dv[X]”refers to the Xth percentile of the particle size distribution.

An acceptable Dv[50] range of particles of aripiprazole lauroxilproduced from the recrystallization process of the present invention is10-30 microns, with a Dv[50] of 10-20 microns being preferred.

The relation of particle size and release rate is further explained inthe studies and examples further below.

Relation of Surface Area and Release Rate

Drug release was found to be proportional to the surface area ofaripiprazole lauroxil produced from the recrystallization process of thepresent invention.

The surface area of recrystallized aripiprazole lauroxil particles canbe measured, for example, using an accelerated surface area andporosimetry analyzer, or by other suitable instruments and methods aswould be well understood by one skilled in the art in light of thepresent disclosure.

An acceptable surface area range for particles of aripiprazole lauroxilproduced from the recrystallization process of the present invention isfrom about 0.50 to about 3.3 m²/g. A surface area range of 0.80 to about1.1 m²/g is preferred, and a surface area of about 1.0 m²/g is morepreferred.

The relation of surface area and release rate is further explained inthe studies and examples further below.

Cooling Profile

FIG. 1 depicts a typical cooling profile for the recrystallizationprocess of the present invention. Cooling of a mixture containingaripiprazole lauroxil, first solvent, and second solvent causes thetemperature of the mixture to decrease, and the mixture becomessupersaturated. Aripiprazole lauroxil precipitates, causing an increasein temperature of the system. This is followed by further cooling of thesystem. As used herein, the term “exotherm” refers to the increase intemperature of the system due to precipitation of the drug. The“precipitation zone,” in which the exotherm occurs, begins when thetemperature starts to increase and covers the entire period during whicharipiprazole lauroxil is precipitating or crystallizing. The “arresttemperature” or target temperature is the temperature at which nofurther decrease in temperature of the system is observed and the start(or onset) of crystallization occurs. Homogenization is preferablyinitiated when the temperature of the supersaturated mixture ofaripiprazole lauroxil is a few degrees above the arrest or targettemperature. Homogenization promotes crystallization and allows forcontrol of particle size and surface area. “Tmin” indicates the initialtemperature increase due to exothermic heating from the majorcrystallization event. Tmin, which defines both the “onset ofcrystallization” and the “onset of exotherm,” is directly correlatedwith particle size and surface area of the recrystallized particles ofaripiprazole lauroxil. “Tmax,” or the exotherm maximum temperature,denotes the completion of significant exothermic heating from the majorcrystallization event. Following the major crystallization event, theslurry is further cooled in the “final cooling” stage (growth zone).“Tmin₂” is the temperature equal to Tmin that occurs upon cooling of thesystem following the exotherm associated with crystallization.

STUDIES AND EXAMPLES

Homogenization

As illustrated in FIG. 2 , homogenizer initiation inducescrystallization at a target temperature. The results of fivecrystallization tests at the 1.75 kg scale are reflected in FIG. 2 . Allof the crystallization tests had the same cooling rate, but each used adifferent homogenizer initiation temperatures and resulted in differentexotherm onset temperatures and, as a result, different crystal sizes.In four of the tests, the homogenizer was turned on at the respectivetemperature specified in the plot, and crystallization was induced soonafter the initiation of homogenization. The Batch 5 test shows the pointwhen spontaneous crystallization occurred, when no homogenization wasused at the given cooling rate.

Impact of Homogenizer Initiation Temperature on Crystal Size (SingleFactor Screening)

The objective of this study was to screen the impact of homogenizationinitiation temperature (“Homogenizer ON”) on the surface area andparticle size of recrystallized aripiprazole lauroxil, as well as thecrystallization induction time and exotherm onset temperature. The studyevaluated homogenizer initiation temperature at three values (35, 36,and 37° C.) while the following parameters were held constant:Homogenizer speed—75% (120 Hz/7200 rpm); Vessel agitation speed—375 rpm;Vessel jacket glycol temperature set-point—30° C. (this parameterdictates the solution primary cooling rate).

Table 1 summarizes several tests at the 4 kg scale used to evaluate theeffect of homogenizer initiation temperature (Homogenizer ON) onin-process crystal particle size. By “exotherm onset temperature” ismeant the temperature at which dissolved aripiprazole lauroxil begins torecrystallize.

TABLE 1 Effect of Homogenizer ON Temperature (4 kg Scale) HomogenizerExotherm ON Onset Temperature Temperature PSD (Micron) Test (° C.) (°C.) Dv[10] Dv[50] Dv[90] B1 37 35.8 6 21 37 B2 36 35.4 5 17 31 B3 3534.7 4 14 29

FIG. 3 shows the temperature profiles for the tests at the 4 kg scale.The plots showed that crystallization (observed by the exotherm)occurred shortly after homogenizer initiation, as was previouslydemonstrated at the 1.75 kg scale (FIG. 2 ).

Impact of Crystallization Variables on Particle Size and Surface Area(Multi-Factor Screening)

The objective of this study was to characterize the impact ofhomogenizer initiation temperature and homogenizer speed on surface areaand particle size as well as the crystallization induction time andexotherm onset temperature. The study evaluated the two factors ofhomogenizer initiation temperature and homogenizer speed, both factorsbeing studied at three levels. The study used a full factorialexperimental design with a center-point resulting in ten (10)crystallizations. The jacket glycol temperature set-point was adjustedas a function of the homogenizer initiation temperature. The intent wasto maintain a heat transfer temperature gradient (at crystallization)between 5-7° C. This value is defined as the difference between thejacket glycol temperature set-point and homogenizer initiationtemperature.

Table 2 summarizes tests from the multi-factor screening study used toevaluate the combinatory effect of homogenizer initiation temperature(Homogenizer ON) and homogenizer speed on in-process crystal surfacearea and particle size. The jacket glycol temperature set-point wasvaried to maintain the gradient in a range of 5-7° C. in order tominimize the under-cooling temperature delta.

FIG. 4 and FIG. 5 present plots of surface area versus exotherm onsettemperature and particle size versus surface area. The plots demonstratethat the strong relationship observed between these attributes at the1.75 kg scale continued to be present at the 4 kg scale.

TABLE 2 Effect of Crystallization Parameters (Multi-factor Screening)Under- Heat Glycol Homg. Exotherm cooling Transfer Jacket Homg. ON OnsetTemp. Temp. Surface Temp. Setting Temp. Temp. Delta Gradient Area PSD(Micron) Test Pattern (° C.) (%) (° C.) (° C.) (° C.) (° C.) (m²/g)Dv[10] Dv[50] Dv[90] C1 31 30 50 37 35.8 1.2 7 0.66 5 19 35 C2 32 30 7537 35.9 1.1 7 0.67 5 19 35 C3 33 30 100 37 37.0 0 7 0.61 8 24 43 C4 1127 50 33 32.7 0.3 6 0.98 4 15 31 C5 0 30 75 35 34.4 0.6 5 0.86 5 17 32C6 13 28 100 33 32.7 0.3 5 0.96 4 13 25 C7 22 30 75 35 34.7 0.3 5 0.87 414 29 C8 21 30 50 35 34.7 0.3 5 0.84 4 16 32 C9 23 30 100 34.5 34.3 0.24.5 0.93 4 16 28 C10 12 27 75 33 32.8 0.2 6 1.04 4 14 26

Impact of Crystallization Variables on Particle Size and Surface Area(Multi-Factor DOE)

The objective of this study was to characterize the impact ofhomogenizer initiation temperature and homogenizer speed on surface areaand particle size as well as the crystallization induction time andexotherm onset temperature. This study was equivalent to the studyImpact of crystallization variables on particle size and surface area(multi-factor screening) above, but executed in a different processtrain. This study evaluated the two factors of homogenizer initiationtemperature and homogenizer speed, each at three levels. The study useda full factorial experimental design resulting in nine (9)crystallizations. The jacket glycol temperature set-point was adjustedas a function of the homogenizer initiation temperature. The intent wasto maintain a heat transfer temperature gradient (at crystallization) of6° C. This value is defined as the difference between the jacket glycoltemperature set-point and homogenizer initiation temperature.

Table 3 summarizes tests from the multi-factor DOE (design ofexperiments) study used to evaluate the combinatory effect ofhomogenizer initiation temperature (Homogenizer ON) and homogenizerspeed on in-process crystal surface area and particle size. The jacketglycol temperature set-point was varied to maintain the gradient at aspecified 6° C. in order to minimize the under-cooling temperaturedelta. The study showed that the impact of Homogenizer ON temperatureand the impact of homogenizer speed parameters were both statisticallysignificant.

TABLE 3 Effect of Crystallization Parameters (Multi-factor DOE) Under-Heat Glycol Homg. Exotherm cooling Transfer Jacket Homg. ON Onset Temp.Temp. Surface Temp. Setting Temp. Temp. Delta Gradient Area PSD (Micron)Test Pattern (° C.) (%) (° C.) (° C.) (° C.) (° C.) (m²/g) Dv[10] Dv[50]Dv[90] D1 13 26 100 32 31.7 0.3 6 1.07 3 13 23 D2 12 26 75 32 31.7 0.3 61.02 4 14 26 D3 23 28 100 34 33.7 0.3 6 0.91 4 16 28 D4 11 26 50 32 31.60.4 6 1.02 3 14 27 D5 21 28 50 34 33.5 0.5 6 0.88 4 17 32 D6 32 30 75 3635.4 0.6 6 0.73 5 19 34 D7 33 30 100 36 35.5 0.5 6 0.77 6 19 34 D8 31 3050 36 35.2 0.8 6 0.69 4 19 35 D9 22 28 75 34 33.6 0.4 6 0.89 3 13 25

Impact of Crystallization Variables on Particle Size and Surface Area(Multi-Factor Augmented DOE)

The objective of this study was to characterize the impact ofhomogenizer initiation temperature, homogenizer speed, and heat transfertemperature gradient (at crystallization) on surface area and particlesize as well as the crystallization induction time and exotherm onsettemperature. This study augmented the foregoing multi-factor DOE studyby incorporating the additional parameter of heat transfer temperaturegradient. The study evaluated the three factors of homogenizerinitiation temperature, homogenizer speed, and heat transfer temperaturegradient (at crystallization), each at three levels. The study used acentral composite experimental design with center-point replicatesresulting in seventeen (17) crystallizations. The jacket glycoltemperature set-point was adjusted as a function of the homogenizerinitiation temperature in order to set the heat transfer temperaturegradient (at crystallization). This value is defined as the differencebetween the jacket glycol temperature set-point and homogenizerinitiation temperature.

Table 4 summarizes tests from the augmented multi-factor DOE study usedto evaluate the combinatory effect of homogenizer initiation temperature(Homogenizer ON), homogenizer speed, and heat transfer temperaturegradient on in-process crystal surface area, particle size, and exothermonset temperature. This DOE augmented the immediately previousexperimental design by including heat transfer temperature gradient as afactor. Again, the jacket glycol temperature set-point was varied tomaintain the gradient at specified values of 4, 6, and 8° C.

FIGS. 6, 7, 8, 9, and 10 show several models built from the results.Table 5 summarizes the findings from these models. All models werestatistically significant based on ANOVA (p-values<0.05) and demonstrateno Lack of Fit.

FIG. 11 shows the relationship between surface area and exotherm onsettemperature. Linear regression analysis demonstrated statisticalsignificance per ANOVA (p-values<0.05). The excellent relationship ofsurface area to exotherm onset temperature was advantageous because itprovided an in-process measurement of crystallization progression orperformance. Advantageously, in the event that the exotherm onsettemperature fell outside the predicted or target range during acrystallization, the run could be discontinued, the material re-heated,and the crystallization repeated.

TABLE 4 Effect of Crystallization Parameters (Multi-factor AugmentedDOE) Heat Under- Homg. Glycol Transfer cooling Exotherm Homg. ON JacketTemp. Temp. Onset Surface Test Setting Temp. Temp. Gradient Delta Temp.Area PSD (Micron) ID Pattern (%) (° C.) (° C.) (° C.) (° C.) (° C.)(m²/g) Dv[10] Dv[50] Dv[90] E1 0a0 75 32 26 6 0.3 31.7 1.02 4 14 26 E2A00 100 34 28 6 0.3 33.7 0.91 4 16 28 E3 a00 50 34 28 6 0.5 33.5 0.88 417 32 E4 0A0 75 36 30 6 0.6 35.4 0.73 5 19 34 E5 0 75 34 28 6 0.4 33.60.89 3 13 25 E6 00a 75 34 30 4 0.1 33.9 0.88 5 18 33 E7 −+− 50 36 32 40.3 35.7 0.68 6 24 43 E8 −−+ 50 32 24 8 0.4 31.6 1.04 4 16 33 E9 +++ 10036 28 8 0.4 35.6 0.81 6 20 33 00 00A 75 34 26 8 0.5 33.5 0.94 5 17 32E11 0 75 34 28 6 0.2 33.8 0.93 5 17 30 E12 −−− 50 32 28 4 0.3 31.7 0.944 18 36 E13 +−+ 100 32 24 8 0.3 31.7 1.13 4 16 30 E14 ++− 100 36 32 40.1 35.9 0.77 6 22 38 E15 −++ 50 36 28 8 0.6 35.4 0.78 6 23 42 E16 0 7534 28 6 0.3 33.7 0.96 5 18 35 E17 +−− 100 32 28 4 0.1 31.9 1.07 4 15 28

TABLE 5 Summary of Multi-factor Augmented DOE Models Lack ANOVA of FIG.R2 (p-value) Fit FIG. 6: Surface area Model 0.849 <0.0001 No(Multi-factor Augmented DOE) FIG. 7: Exotherm Onset 0.990 <0.0001 NoTemperature Model (Multi- factor Augmented DOE) FIG. 8: Particle Size(Dv[10]) 0.599  0.0003 No Model (Multi-factor Augmented DOE) FIG. 9:Particle Size (Dv[50]) 0.574  0.0004 Yes Model (Multi-factor AugmentedDOE) FIG. 10: Particle Size (Dv[90]) 0.340  0.0140 No Model(Multi-factor Augmented DOE)

Characterization of the Process Operational Zone (Multi-Factor DOE)

The objective of this study was to characterize the impact of solutioncooling rate (as a function of jacket glycol temperature),homogenization speed, and crystallization type (spontaneous versusinduced) on the crystallization induction time and exotherm onsettemperature. The study used a designed experiment (central compositedesign) consisting of 10 runs that incorporated two factors at threelevels: Vessel Jacket Temperature (3° C., 16.5° C., 30° C.); andHomogenizer Speed (0%, 37.5%, 75%).

Table 6 summarizes tests from the multi-factor DOE (central compositedesign) consisting of 10 runs that incorporated the two factors at threelevels: Vessel Jacket Temperature (3° C., 16.5° C., 30° C.); andHomogenizer Speed (0%, 37.5%, 75%). Each run that used a 0% homogenizerspeed (no homogenization) was cooled until it spontaneouslycrystallized. In the runs that used homogenizer speeds of 37.5% and 75%,the homogenizer was turned on when the process temperature cooled to53.6° C. (This temperature represents the solubility limit of theprocess solution below which the solution enters a meta-stable state.)The solution then continued to cool with homogenization until itcrystallized. FIG. 12 shows several cooling profiles for runs that usedno homogenization.

An exotherm onset temperature (Tmin) was recorded for each run and thecooling rate was calculated. The process cooling followed an exponentialdecay profile. Therefore, an Exponential Primary Cooling Parameter(i.e., cooling rate) was calculated by plotting the process temperatureas a function of time using the following data transformation method:

$\begin{matrix}{y = {{m*x} + b}} \\{{Where}:} \\{y = {- {{Ln}\left\lbrack \frac{T - {Ta}}{{To} - {Ta}} \right\rbrack}}} \\{{x\lbrack = \rbrack}{{Time}{}\left( {{Min}.} \right)}} \\{{T\lbrack = \rbrack}{Temperature}\left( {{^\circ}{C.}} \right)} \\{{To} = {58{^\circ}{C.}}} \\{{Ta} = {20{^\circ}{}{C.}}}\end{matrix}$

A linear-regression fit of the data resulted in slope-m (1/° C.) andintercept-b, where slope represents the Exponential Primary CoolingParameter. FIG. 13 displays plots of the transformed temperature datafor the corresponding cooling profiles from FIG. 12 .

TABLE 6 Process Operational Zone Results Exponential Homg. GlycolPrimary Exotherm Homg. ON Jacket Cooling Onset Induction Test SettingTemp. Temp. Parameter Temp. Time ID (%) (° C.) (° C.) (1/min) (° C.)(min) F1 0 N/A 3 0.30 25.4 6.2 F2 0 N/A 16.5 0.18 25.7 9.8 F3 0 N/A 300.08 32.7 15.6 F4 37.5 53.6 3 0.26 33.2 3.6 F5 37.5 53.6 16.5 0.18 34.95.4 F6 37.5 53.6 16.5 0.18 35.2 4.7 F7 37.5 53.6 30 0.10 37.4 7.4 F8 7553.6 3 0.25 32.6 4.1 F9 75 53.6 16.5 0.17 34.7 5.3 F10 75 53.6 30 0.0937.4 8.3

FIG. 14 shows a plot of exotherm onset temperature (Tmin) versus thecalculated Exponential Primary Cooling Parameter (i.e., cooling rate).The following terms describe key features of the plot:

Solubility Limit: The temperature at which the process solution becomessaturated. Below this temperature, the solution is supersaturated. Thesupersaturated solution is kinetically persistent since it is changingrelatively slowly but has not yet reached thermodynamic equilibrium,which results in crystallization.

Lower Operating Boundary: The lowest process temperature the system canachieve at a specified cooling rate prior to spontaneous crystallization(i.e., crystallization in the absence of homogenization).

Upper Operating Boundary: The highest process temperature the system canachieve at a specified cooling rate prior to forced crystallization(i.e., crystallization that occurs in the presence of homogenization).In this case, homogenization was initiated immediately after thesolution cooled to the solubility limit (53.6° C.), thereby impartingthe maximum homogenization time within the meta-stable zone.

Operational Zone: The temperature range available to the system for aspecified cooling rate where crystallization of the supersaturatedsolution can be induced through homogenization at a target temperature.The operational zone provided guidance for selection of optimum targetcooling rate and exotherm onset temperature (Tmin) combinations, whichresulted in robust processing to target surface areas.

Additional Synthesis Examples

200 Gram Scale

Aripiprazole lauroxil was recrystallized using the following procedure.246.4 g of isopropyl acetate was heated in a 1 liter Erlenmeyer flask to70-75° C. 383.0 g of heptane was heated in a 1 liter Erlenmeyer flask to45-50° C. The hot isopropyl acetate was added to a 2 liter Erlenmeyerflask containing 200 g of aripiprazole lauroxil. The mixture was heatedwith swirling until all the white solids dissolved and a clear solutionwas obtained at 65-70° C. Hot heptane was added to the clear solution inthree portions with gentle heating and swirling to avoid crash-out.

The flask containing the clear solution was placed in a 12 inch sievepan or equivalent. A homogenizer probe was placed into the solution andturned on to #3 (13.5 l/min set on the machine). Ice was added up to thecapacity of the pan. The homogenizer was stopped once the solutioncrystallized. The flask was kept in ice until the temperature was 15-20°C. The flask was removed from the ice bath.

A filtration set-up was assembled using a 2 liter filtering flask,Buchner funnel with a rubber connector, and filter paper. The filterpaper was wetted with heptane (˜5 ml). The recrystallized white solidwas filtered and washed with heptane (˜60 ml).

The filtered material was spread into a dish. The material was driedinside a vacuum oven at room temperature for 18-24 hrs with a nitrogenpurge. The dried material was transferred into a 250 μm sieve. 5 PTFEsieve rings were added to the sieve, a cover with o-ring was placed onthe sieve, and sieving took place using an Analysette 3 PRO at anamplitude set point of 2.7.

Four batches were made following this procedure and combined together toprepare a suspension of aripiprazole lauroxil. Table 7 lists theparticle size distribution summary statistics for each batch as well asthe combined (weight averaged) final batch. FIG. 15 shows the particlesize distributions for each batch as well as the combined (weightaveraged) final batch.

TABLE 7 Particle size distribution summary statistics (post dry andsieving) Dv[10], Dv[50], Dv[90], Batch μm μm μm % Total UM1 3 17 39 23.5UM2 4 20 42 22.4 UM3 4 23 45 22.1 UM4 3 14 33 32.0 UM Average 3 18 39100

Modified 200 Gram Scale

Using a graduated cylinder, 280 ml of isopropyl acetate were measuredand transferred to a 2 liter Erlenmeyer flask. Using a graduatedcylinder, 560 ml of n-heptane were measured and mixed with the measuredisopropyl acetate. 200 g of aripiprazole lauroxil were weighed into a 2liter Erlenmeyer flask. The solvent mixture was heated to 70° C. andthen added to the aripiprazole lauroxil containing flask. The slurry washeated back to 65° C. to obtain a clear solution.

The solution was then poured into a 1 liter jacketed glass vessel with afirst recirculator recirculating water and an overhead high shear mixingprobe. The probe was turned on immediately on setting #3 (13.5 l/min seton the machine). As soon as the internal temperature reached 2° C. abovethe target arrest temperature, the recirculating water was switched to asecond recirculator in order to arrest the cooling. As soon as thetemperature started to rise the time was noted and the recirculatingwater was switched back to the first recirculator. The probe was thenstopped 90 seconds after the start of the temperature rise, after whichit was replaced with an overhead mixer. The slurry was left to cool downto 18° C.

When the slurry reached 18° C. the slurry was filtered using a Buchnerfunnel with Whatman filter paper 4. The solids were then washed withapproximately 100 ml of n-heptane. The solids were spread into acrystallization dish and left to dry in a vacuum oven at roomtemperature, house vacuum, and a nitrogen purge for approximately 18hours.

TABLE 8 Differences between 200 g scale and modified 200 g scaleprocesses 200 gram scale Modified 200 gram process Drug Aripiprazolelauroxil is dissolved in Aripiprazole lauroxil is dissolved indissolution 70-75° C. isopropyl acetate and then a 65° C. isopropylacetate/heptane 45-50° C. heptane is added. mixture. Crystallization 2liter Erlenmeyer flask in an ice 1 liter jacketed glass vessel with twovessel bath. recirculating jacket fluid temperatures. Mixing Manualswirling and homogenizer. Overhead mixer and homogenizer.Crystallization Homogenizer is switched on and Homogenizer is switchedon and solution is cooled with ice bath until solution cooled withrecirculator 1. it reaches 15-20° C. As soon as the internal temperatureHomogenizer is switched off once reached 2° C. above the target arrestthe solution crystallizes. temperature, the recirculating water isswitched to recirculator 2 in order to arrest the cooling. As soon asthe temperature started to rise the time the recirculating water isswitched back to recirculator 1 until the slurry reaches 15-20° C.Homogenizer is switched off 90 s after the start of the temperaturerise, after which it is replaced with an overhead mixer.

The modified 200 gram process was used successfully in four aripiprazolelauroxil recrystallization batch campaigns (each consisting of fiverecrystallization batches). A particle size distribution similar to thatfrom the (unmodified) 200 gram process was reproducibly obtained as seenin FIG. 16 . Summary statistics are listed in Table 9. A comparisonbetween the particle size distribution statistics of recrystallizedaripiprazole lauroxil from the modified process versus that from theunmodified process revealed a tighter spread in Dv[10], Dv[50], andDv[90], clearly showing an improvement in process robustness andreproducibility.

TABLE 9 Particle size distribution summary statistics of four batchcampaigns Batch Dv[10], μm Dv[50], μm Dv[90], μm M1 5 21 36 M2 4 20 34M3 6 21 35 M4 6 23 39 M5 6 23 39 2 A 6 21 36 2 B 6 23 39 2 C 7 26 42 2 D7 23 38 2 E 5 21 36 3 A 7 24 40 3 B 6 23 39 3 C 6 22 38 3 D 6 23 39 3 E6 23 41 4 A 6 22 37 4 B 6 24 39 4 C 4 20 34 4 D 4 21 37 4 E 4 22 37Range 4-7 20-26 34-42 Mean 6 22 38 Rel. SD 17% 7% 6%

1.75 kg Scale

Aripiprazole lauroxil was recrystallized using the following procedure.2156.0 g of isopropyl acetate was added to a recrystallization vesselcontaining 1750.0 g of aripiprazole lauroxil. The mixture was heatedunder agitation to 55-65° C. When the drug was visibly dissolved insolution, 3351.0 g of heptane heated to 55-65° C. was added to therecrystallization vessel. The resulting mixture was heated to 60-65° C.,at which point cold glycol was introduced into the jacket of therecrystallization vessel in order to cool the mixture. When thetemperature of the mixture of isopropyl acetate, heptane, andaripiprazole lauroxil reached 34° C., homogenization was initialized.The temperature was continuously monitored for the onset of the exotherm(start of precipitation or crystallization) and the exotherm maximum.When the mixture temperature reached the value Tmin after the exotherm(Tmin₂), homogenation was stopped. More cold glycol was introduced intothe vessel jacket in order to cool the mixture to 18° C., at which pointthe mixture was held for 5 minutes.

Then, hot glycol was introduced into the vessel jacket to reheat themixture toward 60-65° C., at which point cold glycol was againintroduced into the jacket of the recrystallization vessel in order tocool the mixture. When the temperature of the mixture of isopropylacetate, heptane, and aripiprazole lauroxil reached 34° C.,homogenization was initialized. The temperature was continuouslymonitored for the onset of the exotherm and the exotherm maximum. Whenthe mixture temperature reached the value Tmin after the exotherm(Tmin₂), homogenation was stopped. More cold glycol was introduced intothe vessel jacket in order to cool the mixture to 18° C. Therecrystallized aripiprazole lauroxil was filtered under vacuum in a deadend filter dryer and rinsed with 2187.0 g of heptanes at ambienttemperature. The solids were dried under vacuum (80 torr) for 40 hoursin the same vessel and collected.

4 kg Scale

Aripiprazole lauroxil was recrystallized using the following procedure.4940.0 g of isopropyl acetate was added to a recrystallization vesselcontaining 4000.0 g of aripiprazole lauroxil and mixture underagitation. When the drug was visibly dissolved in solution (≥55° C.),7670.0 g of heptane heated to 55-65° C. was added to therecrystallization vessel. The resulting mixture was heated to ≥60° C.and then held for 5 minutes. Cold glycol (28° C.) was then introducedinto the jacket of the recrystallization vessel in order to cool themixture, and when the temperature of the mixture of isopropyl acetate,heptane, and aripiprazole lauroxil reached 33.8° C., homogenization wasinitialized. The temperature was continuously monitored for the onset ofthe exotherm (start of precipitation or crystallization) and theexotherm maximum. (If Tmin was less than 33° C., then another cycle ofrecrystallization was performed.) When the mixture temperature reachedthe value Tmin after the exotherm (Tmin₂), the homogenation was stopped.More cold glycol was introduced into the vessel jacket in order to coolthe mixture to 18° C.

Then, hot glycol was introduced into the vessel jacket to reheat themixture toward 60-65° C., at which point cold glycol was againintroduced into the jacket of the recrystallization vessel in order tocool the mixture. When the temperature of the mixture of isopropylacetate, heptane, and aripiprazole lauroxil reached 33.8° C.,homogenization was initialized. The temperature was continuouslymonitored for the onset of the exotherm and the exotherm maximum. Whenthe mixture temperature reached the value Tmin after the exotherm(Tmin₂), homogenization was stopped. More cold glycol was introducedinto the vessel jacket in order to cool the mixture to 18° C. Therecrystallized aripiprazole lauroxil was filtered under vacuum in a deadend filter dryer and rinsed with 9 kg of heptanes at ambienttemperature. The solids were dried under vacuum (20 torr) for 20 hoursin the same vessel and collected.

Example Using Sonication Instead of Homogenization

Aripiprazole lauroxil (10 g) was dissolved in hot isobutyl acetate (14mL). N-heptane (28 mL) was added to the hot solution and the mixture washeated further to dissolve all solids. The hot solution was placed in asonication bath and sonicated for 2 minutes. Ice was added to thesonication bath to cool down the mixture. White crystals were formed.The crystals were filtered using a Buchner funnel and washed with coldn-heptane (10 mL). The white solid was then dried under vacuum at roomtemperature overnight and resulted in 9.6 g of recrystallizedaripiprazole lauroxil (96% yield).

Impact of Aripiprazole Lauroxil Particle Size Distribution (PSD),Surface Area, and Vehicle on In Vivo Release Profiles

In order to explore the effect of injection vehicle on aripiprazoleplasma exposure, a single-dose IM (intramuscular) rat dosing study wasconducted. The dosing amount in the study was 29 mg of recrystallizedaripiprazole lauroxil prodrug, which is equivalent to 20 mg aripiprazolebase. The following two formulations were prepared and dosedintramuscularly to male rats:

-   -   (1) aripiprazole lauroxil bulk recrystallized drug substance        suspended in a phosphate-buffered saline injection vehicle with        sodium carboxymethylcellulose (NaCMC) (2 wt %) and polysorbate        20 (0.2 wt %); and    -   (2) aripiprazole lauroxil recrystallized drug substance        suspended in a phosphate-buffered saline injection vehicle using        sorbitan monolaurate (SML) (0.5 wt %) and polysorbate 20 (0.2 wt        %).

FIG. 17 shows pharmacokinetic profiles of aripiprazole resulting fromintramuscular administration of a single dose of recrystallizedaripiprazole lauroxil (20 mg aripiprazole equivalents) suspended ineither the NaCMC or SML vehicle, to male rats to assess the effect ofinjection vehicle on the in vivo profile. Two lots of recrystallizedaripiprazole lauroxil drug substance were tested. Pharmacokineticanalysis showed that suspensions prepared from the same drug substancelot resulted in essentially overlapping in vivo pK profiles ofaripiprazole, independent of injection vehicle. The pK parameters,summarized in Table 10, indicated that the injection vehicle did notsignificantly impact C_(max), T_(max), or AUC_(0-Tlast).

TABLE 10 pK parameters from a single IM administration of recrystallizedaripiprazole lauroxil in male rats drug substance C_(max) T_(max)AUC_(0-Tlast) ^(c) lot, vehicle (ng/mL) ^(a) (day) ^(b) (day*ng/mL) LotA, suspended in 34.2 ± 6.21 13.8 ± 3.66 735 ± 82.7 NaCMC vehicle Lot A,suspended in 43.1 ± 8.60 16.0 ± 1.55 836 ± 73.0 SML vehicle Lot B,suspended in 22.7 ± 1.17 17.2 ± 5.74 638 ± 53.7 NaCMC vehicle Lot B,suspended in 23.4 ± 6.47 17.2 ± 3.66 643 ± 146 SML vehicle ^(a) C_(max):The maximum precipitated plasma concentration observed. ^(b) T_(max):Time at which C_(max) occurred. ^(c) AUC_(0-tlast): Area under theprecipitated plasma concentration-time curve from Time 0 to the lastmeasured precipitated plasma concentration.

The impact of the particle size distribution (PSD) and surface area onaripiprazole pK was further investigated using four lots ofrecrystallized aripiprazole lauroxil in the rat IM pK model at the samedose of 29 mg aripiprazole lauroxil equivalent to 20 mg of aripiprazole.PSD and surface area measurements for the four lots are presented inTable 11, and the PSD profiles are illustrated in FIG. 18 .

TABLE 11 PSD and surface area measurements fo raripiprazole lauroxilbulk recrystallized drug substance lots Dv[10] Dv[50] Dv[90] Surfacearea Lot # μm^(a) μm^(a) μm^(a) (m²/g) X2 3 15 35 0.73 X1 3 9 24 1.10 X33 8 20 1.32 X4 3 12 30 Not measured ^(a)For a single preparation andmeasurement, PSD method error for the volume metrics are: Dv[10] = ±0.9μm, Dv[50] = ±3.5 μm, and Dv[90] = ±5.7 μm. For an average of threepreparations and measurements, PSD method error would be Dv[10] = ±0.5μm, Dv[50] = ±2.0 μm, and Dv[90] = ±3.3 μm.

To examine the influences of the PSD and surface area on aripiprazolepK, the characterized lots of recrystallized aripiprazole lauroxillisted in Table 11 were suspended in SML vehicle and administered by IMadministration to male rats. The aripiprazole pK profiles are plotted inFIG. 19 , and the pK parameters are presented in Table 12. These datashow that material with a smaller PSD and increased surface area (i.e.,lot X3) will result in faster release rates (FIG. 19 , top-most curve).(Release rate is expressed as aripiprazole plasma exposure (dependent onboth the rate of dissolution of recrystallized aripiprazole lauroxil andthe rate of esterase mediated conversion of aripiprazole lauroxil toaripiprazole). Material with larger PSD and decreased surface area(i.e., lot X2) will result in slower release rates (FIG. 19 ,bottom-most curve). Importantly, examination of the calculated AUC_(inf)indicates that systemic exposure was similar for all groups in thisexperiment.

TABLE 12 Aripiprazole pK parameters following a single IM administrationof recrystallized aripiprazole lauroxil suspended in SML injectionvehicle in male rats Surface area C_(max) ^(a) T_(max) ^(b)AUC_(0−tlast) ^(c) AUC_(inf) ^(d) Drug Lot Group (m²/g) (ng/mL) (day)(day*ng/mL) (day*ng/mL) Lot X3 C 1.32 Mean 43.1 16.0 836 894 SD 8.601.55 73.0 91 Lot X1 A 1.10 Mean 35.0 15.5 817 1050 SD 6.76 3.73 66.7 157Lot X4 D Not Mean 28.9 16.0 713 952 measured SD 6.23 1.55 153.0 282 LotX2 B 0.73 Mean 23.4 17.2 643 918 SD 6.47 3.66 146.0 184 ^(a) C_(max):The maximum precipitated plasma concentration observed. ^(b) T_(max):Time at which C_(max) occurred. ^(c) AUC_(0−tlast): Area under theprecipitated plasma concentration-time curve from Time 0 to the lastmeasured precipitated plasma concentration. ^(d) AUC_(inf): Area underthe precipitated plasma concentration-time curve from Time 0 toinfinity.

The conclusions from these experiments are that both PSD and surfacearea measurements were important aspects of the physical propertycharacterization of the aripiprazole lauroxil drug crystals. Consistentwith a release mechanism that is dominated by crystal dissolution, thedata obtained from these pK studies highlight the rank order with regardto surface areas and pK profiles. This ordering is consistent with thecharacter of the insoluble prodrug crystals, namely, that the particlesize distribution and surface area of aripiprazole lauroxil are the keyattributes influencing in vivo performance.

In conclusion, as demonstrated in the pK studies described above, theperformance of recrystallized aripiprazole lauroxil drug product wasdominated by the physical properties of the product crystals.Dissolution of aripiprazole lauroxil following injection was limited byslow dissolution of the drug crystals, and was a function of the amountof exposed surface area of the aripiprazole lauroxil material. Theparticle size distribution and surface area of aripiprazole lauroxilwere the key attributes influencing in vivo performance.

Two-Pass Recrystallization

A two-pass recrystallization process was developed to further improvereproducibility and particle size control.

As described earlier, crystallization of aripiprazole lauroxil occursafter cooling the mixture of the drug, the first solvent (such asisopropyl acetate), and the second solvent (such as n-heptane) to asupersaturated condition. Control of the solution temperature to targeta specific onset temperature (exotherm “Tminimum” or “Tmin”) forcrystallization is important to control the final particle sizedistribution and surface area of the aripiprazole lauroxil crystals.Nucleation and crystallization can be induced by initiating high-shearmixing as the supersaturated mixture approaches a target temperature.The recrystallization process of the present invention reproduciblyproduces crystals of aripiprazole lauroxil with desirable particle sizedistribution and surface area parameters.

Subsequent to the studies described above involving one-passrecrystallization or a single pass of recrystallization, additionalstudies were performed in ultra-clean equipment.

In sterile pharmaceutical manufacturing, processing is conducted inultra-clean equipment to ensure quality and reduce contamination.Equipment is cleaned and steam sterilized in place before use. Surfacefinish is controlled to be very smooth to aid in cleaning. Aftercleaning and during use, equipment must be kept totally closed to theenvironment to prevent contamination. A first pass of recrystallizationmay not always behave as predictably as desired. For instance, variationin crystallization onset time or crystallization temperature may beunacceptably large, resulting in recrystallized particles that havesub-optimal particle size distribution and surface area parameters.Moreover, since the process is conducted in totally closed equipment,conventional means of adding solid crystals to facilitatecrystallization can be highly impractical.

Accordingly, a process to further facilitate reproduciblerecrystallization of aripiprazole lauroxil was developed. Crystals ofaripiprazole lauroxil were first formed by cooling and precipitating atsupersaturated conditions with or without homogenization. The solutionwas then re-warmed and the crystals were re-dissolved. When the solutionwas re-cooled, crystals were precipitated in a reliable manner, with theaid of high-shear mixing as the target temperature was approached, muchas in the one-pass crystallization process described earlier.

In replicate experiments, the first pass recrystallization resulted inlarge variation in time from homogenizer onset to crystal formation.Time to crystallization ranged from about 1 minute to over 37 minutes. Alarger variation in crystallization Tmin was noted. Results of firstpass recrystallization are shown in Table 13.

TABLE 13 Induction time Crystallization (Crystallization Homogenizeronset onset time- ON Sample Crystallization Homogenizer (Tmin)homogenizer temperature, Tmin, # pass ON time time on time) ° C. ° C. Z11 17:46 34:00 16:14 35 31.3 Z2 1 16:37 17:35  0:58 35 34.6 Z3 1 17:0654:59 37:53 35 29.5

After seeding, the subsequent second pass of recrystallization occurredquickly and reproducibly around 1 minute or less after homogenizationonset. A much smaller variation in Tmin was achieved. Results of thesecond pass of recrystallization are shown in Table 14.

TABLE 14 Induction time (Crystallization Homogenizer Crystallizationonset time- ON Sample Crystallization Homogenizer onset (Tmin)homogenizer temperature, Tmin, # pass ON time time on time) ° C. ° C. Z12 17:03 18:05 1:02 35 34.6 Z2 2 17:03 17:50 0:47 35 34.6 Z3 2 17:2217:49 0:27 35 34.8

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood inlight of the present disclosure by those skilled in the art that variouschanges in form and details may be made therein without departing fromthe scope of the invention encompassed by the appended claims.

What is claimed is:
 1. A process for making a compound of Formula (I) incrystal form:

the process comprising the steps of: (a) dissolving the compound ofFormula (I) or a salt or solvate thereof in a first solvent to form ahomogeneous drug solution; (b) optionally combining the drug solutionwith a second solvent; (c) cooling the solution; and (d) furtherhomogenizing the solution to induce formation of the compound of Formula(I) in crystal form.
 2. The process of claim 1, further comprising thesteps of: (e) stopping the homogenization, and re-dissolving thecompound of Formula (I) in crystal form by heating the solution; (f)cooling the solution; and (g) further homogenizing the solution toinduce formation of the compound of Formula (I) in crystal form.
 3. Theprocess of claim 1, wherein the crystallized particles have a surfacearea of about 0.50 to about 3.3 m²/g.
 4. The process of claim 1, whereinthe crystallized particles have a surface area of about 0.80 to about1.1 m²/g.
 5. The process of claim 1, wherein the crystallized particleshave a surface area of about 1.00 m²/g.
 6. The process of claim 1,wherein the Dv[50] of the crystallized particles is about 10 to about 30microns.
 7. The process of claim 1, wherein the Dv[50] of thecrystallized particles is about 10 to about 20 microns.
 8. The processof claim 1, wherein in step (a), the first solvent is isopropyl acetate.9. The process of claim 1, wherein in step (a), the first solvent is amixture of isopropyl acetate and n-heptane.
 10. The process of claim 1,wherein in step (b), the second solvent is n-heptane.
 11. The process ofclaim 1, wherein in step (b), the solution is at a temperature in therange of about 55° C. to about 65° C.
 12. The process of claim 1,wherein in step (d), the solution is at a temperature within the rangeof about 31-38° C.
 13. The process of claim 1, wherein in step (d), thesolution is at a temperature within the range of about 31-35° C.
 14. Theprocess of claim 1, wherein in step (d), the solution is at atemperature of about 34° C.
 15. The process of claim 1, wherein one ormore of steps (a) through (c) is performed under agitation.
 16. Theprocess of claim 2, wherein one or more of steps (a), (b), (c), (d),(e), (f), and (g) is performed under agitation.
 17. The process of claim1, wherein the process further comprises the step of filtering thecrystallized particles.
 18. The process of claim 17, wherein the processfurther comprises the step of rinsing the crystallized particles. 19.The process of claim 18, wherein the process further comprises the stepof drying the crystallized particles.
 20. The process of claim 1,wherein the solution of step (d) is further homogenized by ahomogenizer.